7. PROJECT SUMMARY Multiple myeloma, a disease in which malignant plasma cells reside in the bone marrow, is the second most prevalent hematologic malignancy in the United States. Over 26,000 new cases are diagnosed and over 11,000 die from myeloma each year. Myeloma is a devastating cancer marked by fatigue, intractable bone pain, renal failure and recurrent infections. The emergence of new therapies (e.g., bortezomib, thalidomide) over the past decade has greatly improved survival rates; yet the overall outlook for patients remains grim as these therapies slow rather than cure the disease and patients ultimately relapse, then rapidly decline. Thus, discovering new targets and their inhibitors, especially for relapsed patients, is a high priority. Key interactions within the bone marrow stroma are critical for myeloma cell invasion and survival, including stimulating angiogenesis that supports tumor growth and metastasis. We have recently discovered three novel mechanisms, complemented by three highly promising inhibitors, that govern myeloma cell invasion, survival, the angiogenesis upon which they depend and a novel mechanism of immune suppression by the tumors. All three mechanisms rely on syndecan-1 (Sdc1, CD138), a cell surface heparan sulfate proteoglycan that is highly expressed in myeloma and correlates with poor prognosis in this disease. The three mechanisms involve insulin-like growth factor receptor (IGF1R), which is critical for the survival of myeloma cells, VLA4 (the ?4?1 integrin) that the myeloma cells rely on for extravasation, interactions in the bone marrow necessary for growth and survival and drug resistance, and vascular endothelial growth factor receptor-2 (VEGFR2), which we have recently shown drives the invasion of heparanase-expressing myeloma cells, but also appears to suppress recruitment of NK- and cytotoxic T-cells. In each of these cases, the mechanism is also expressed and active on endothelial cells providing the tumor with a blood supply and metastatic outlets. Each of these important receptors is coupled to the extracellular domain of Sdc1 and their function is blocked by highly stable peptides (synstatins) that we are developing as potential therapeutics for myeloma. We propose in this application to investigate the molecular underpinnings of these mechanisms, and to test our peptides as potential new therapeutics in rigorous mouse models of multiple myeloma.